1. Field of Invention
This invention relates to novel compositions of matter for topical application to humans and methods for providing therefrom a controlled dosage of 17-.beta.-estradiol. The novel compositions comprise estradiol and a polymer in a form adapted for the slow and gradual release of the medicament so that the concentration of drug in the blood plasma of the patient is maintained within levels desirable for optimum clinical efficacy.
2. Description of the Prior Art
Knowledge of the endocrinological role of estradiol dates from the early part of this century. Its relation to the menstrual cycle was established in the 1920s and its chemical structure was elucidated in the 1930s.
When the ovaries do not function properly due to age, i.e. menopause, or disease, or have been removed, the consequent lack of endogenous estradiol may produce a number of symptoms, such as hot flashes, pain and increased hypocalcemia, eventually leading to osteoporosis.
One way of avoiding or alleviating these symptoms is by estrogen replacement therapy, i.e. by giving a compensatory dose of estrogen to the patient. This treatment is not without danger, since it has been established by various researchers that in women taking exogenous estrogens, there is an increased risk of endometrial cancer, estimated to be between 4.5 to 13.9 times greater than in women not taking exogenous estrogen. The risk is related to dosage and duration of use. Other side effects due to the intake of estradiol may be cholelithiasis (gall bladder disease) and thromboembolic disease due to increase in lipoproteins and triglycerides in the blood.
As a result of the increase in the average age of the human population during the last few decades, there are more female patients suffering from post-menopausal symptoms and osteoporosis and, therefore, there is a growing need for this form of therapy. However, due to the sometimes dangerous side effects mentioned hereinbefore, treatment requires a very fine tuning of the dosage, i.e. the blood levels of the drug are kept at the minimum required for clinical efficacy.
The concentration of estradiol required for clinical effectiveness has been shown to be between 50 and 120 picograms per milliliter (pg/l) of plasma. At 60 pg/l a reduction of about 50% of the hot flashes was observed and at about 120 pg/ml they totally disappeared.
Various methods are in use or have been proposed for the estradiol replacement therapy, e.g. tablets, aqueous suspensions for injection, implants and patches for transdermal application.
Oral therapy, using tablets, is most convenient for the patient but the effect is rather short since the half-life of estradiol in the plasma is only one hour and up to three doses per day may be required to maintain therapeutically effective levels. The first pass inactivation of estradiol is very high, its oral availability being only about 30%. This leads to accumulation in the body of large quantities of estrone and other estrogens.
Resetarits et al (International Journal of Pharmaceutics, 2, 113-123 (1979) reported that the dissolution rate of estradiolpolyvinylpyrrolidone "coprecipitates", prepared by dissolving both components in ethanol and subsequently removing the solvent in vacuo, was appreciably higher than that of microcrystalline estradiol. There was no evidence that estradiol and polyvinylpyrrolidone formed complexes in the solid state and it was concluded that in the "coprecipitate" the estradiol exists in a more water-soluble, high energy form of the drug. It was suggested that this may increase the systemic availability of the estradiol and reduce the extensive pre-systemic metabolism after oral administration.
The use of parenteral injections and implants or pellets, while avoiding the first pass loss, is much less convenient for the patient and, therefore, the use of these forms of therapy is not popular.
The administration of estradiol from a dosage form adapted for nasal delivery, e.g. solutions, suspensions, gels and ointments is disclosed in U.S. Pat. No. 4,383,993. The dosage form consists of estradiol and a pharmaceutically acceptable nasal carrier, e.g. a mixture of water, an emulsifier and, if desired, a gelling agent.
Estradiol, like other estrogens, is readily absorbed through the skin and since, as indicated hereinbefore, very low concentrations (around 100 pg/ml) are required for clinical efficacy, this renders it an excellent candidate for transdermal application. Schenkel, Barlier, Riera and Barner (Journal of Controlled Release, 4, 195-201 (1986) have shown that transdermal application of estradiol to different body sites results in comparable absorption.
Patches for transdermal application generally involve membrane-control of the delivery of the drug. U.S. Pat. No. 4,379,454 discloses an adhesive patch in which estradiol and ethanol simultaneously permeate through an ethylene-vinyl acetate copolymer membrane from a gelled estradiol-ethanol mixture which is in contact with the membrane. The ethanol enhances the rate of percutaneous absorption of the estradiol.
Transdermal delivery systems for estradiol have been reviewed by Good, Powers, Campbell and Schenkel (Journal of Controlled Release, 2, 89-97 (1985) and Guy and Hadgraft (Journal of Controlled Release, 4, 237-251 (1987).
The factors affecting the diffusion of steriods, including estradiol, through crosslinked polydimethylsiloxane membranes have been reported by Lacey and Cowsar in "Controlled Release of Biologically Active Agents", Tanquary and Lacey, eds, Plenum Press, New York, pp. 117-144 (1974).
The present invention is directed towards improvements in the transdermal delivery of estradiol wherein compositions containing the steroid, upon topical application, will provide a slow and sustained release of the estradiol so as to maintain the desired level of the drug in the blood of the patient. This is accomplished by the incorporation of uncrosslinked, water-insoluble vinylpyrrolidone copolymers in the compositions.
The use of water-soluble polyvinylpyrrolidone in conjunction with various medicaments has been disclosed in a number of patents. Thus, German DOS 2,301,664 and British Patent No. 1,427,881 disclose the prolongation of the storage stability of nitroglycerin by the addition of polyvinylpyrrolidone. U.S. Pat. No. 4,091,091 describes the stabilization of nitroglycerin against tablet-to-tablet migration by the incorporation of water-soluble polyvinylpyrrolidone in the mixture of a water-soluble excipient and nitroglycerin, while retaining the rapid solubility of the tablet in the mouth.
The release of nitroglycerin as a result of the water-solubility of vinylpyrrolidone homopolymer or copolymers has also been utilized in an antianginal film or plate. Thus, British Patent Application No. 2021610A discloses that a thin film containing nitroglycerin, a water-soluble homopolymer or copolymer of acrylamide and/or vinylpyrrolidone and, optionally a dispersed solid fat, is applied to a site in the mouth and releases the medicament at a rate which is dependent upon the rate of solution of the polymer.
The prior art teaches that water-soluble vinylpyrrolidone homopolymer complexes with nitroglycerin in a solid tablet or film and reduces the volatility and migration of the medicament without reducing the availability of the drug in an aqueous environment.
U.S. Pat. No. 4,482,534 discloses that the incorporation of water-insoluble vinylpyrrolidone homopolymer or copolymers in an ointment, gel or film containing nitroglycerin provides increased stability and reduced volatility of the nitroglycerin, while permitting slow release of the drug when applied topically to the skin.
The use of water-soluble polyvinylpyrrolidone in conjunction with medicaments other than nitroglycerin has been disclosed in a number of patents. Thus, U.S. Pat. No. 3,972,995 discloses a buccal dosage form in which the water-soluble homopolymer functions as a binder in an adhesive layer. U.S. Pat. No. 3,214,338 discloses a topical ointment in which the water-soluble homopolymer is added to an emulsifiable polyvinyl acetate powder. U.S. Pat. No. 3,803,300 discloses a film-forming ointment containing water-soluble vinylpyrrolidone homopolymer or copolymers. U.S. Pat. No. 3,287,222 discloses the use of the homopolymer as a water-soluble plasticizer in an impregnating solution for a synthetic fiber medical dressing. U.S. Pat. No. 4,210,633 discloses a water-soluble medicated film containing the water-soluble homopolymer. U.S. Pat. No. 3,608,070 discloses a surgical dressing which is an ointment containing a vinylpyrrolidone copolymer, a thixotropic agent, a water-soluble plasticizer and a solvent such as aqueous ethanol. The film formed on drying the ointment is readily soluble in water. U.S. Pat. No. 2,776,924 discloses the use of water-soluble polyvinylpyrrolidone to inhibit adverse reactions from therapeutic agents in topical application.
In these prior art disclosures with medicaments other than nitroglycerin, vinylpyrrolidone polymers are used because of their film-forming ability and/or water solubility. The rapid solubilization of the polymer results in rapid release of the medicament.
The prior art discloses that the use of water-insoluble, crosslinked polyvinylpyrrolidone also promotes the rapid release of medicament. Thus, British Patent No. 1,380,171 discloses the use of crosslinked, water-insoluble polyvinylpyrrolidone in medicinal tablets containing a drug, to promote rapid disintegration of the tablet in aqueous fluids and increase the availability of the drug. Examples are provided which illustrate that the presence of water-insoluble polyvinylpyrrolidone results in more rapid disintegration and release of the drug as compared with the water-soluble polymer. German Patent Application 2,634,004 discloses the use of crosslinked, insoluble polyvinylpyrrolidone as a carrier material for poorly soluble medicaments in order to accelerate the release thereof when administered orally. German Patent Application 1,467,792 discloses the use of crosslinked polyvinylpyrrolidone as a disintegration agent to increase the rate of disintegration of a tablet to promote the extremely rapid release of the drug therein in the digestive tract.